Leflunomide - How It Works
Clinical pharmacology details from the US FDA-approved label: how Leflunomide works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity.
Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect.
12.3 Pharmacokinetics Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity.
Plasma concentrations of the parent drug, leflunomide, have been occasionally seen at very low concentrations.
Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of the active metabolite, teriflunomide.
Absorption Following oral administration, peak teriflunomide concentrations occurred between 6 to 12 hours after dosing.
Due to the very long half-life of teriflunomide (18 to 19 days), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations.
Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require about two months of dosing.
The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional.
Effect of Food Coadministration of leflunomide tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations.
Distribution Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma.
The volume of distribution is 11 L after a single intravenous (IV) administration.
Elimination Teriflunomide, the active metabolite of leflunomide, has a median half-life of 18 to 19 days in healthy volunteers.
The elimination of teriflunomide can be accelerated by administration of cholestyramine or activated charcoal .
Without use of an accelerated drug elimination procedure, it may take up to 2 years to reach plasma teriflunomide concentrations of less than 0.02 mg/L, due to individual variation in drug clearance [see Warnings and Precautions ] .
After a single IV administration of the metabolite (teriflunomide), the total body clearance of teriflunomide was 30.5 mL/h.
Metabolism In vitro inhibition studies in human liver microsomes suggest that cytochrome P450 (CYP) 1A2, 2C19 and 3A4 are involved in leflunomide metabolism.
In vivo, leflunomide is metabolized to one primary (teriflunomide) and many minor metabolites.
In vitro, teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase enzymes.
The parent compound is rarely detectable in plasma.
Pharmacokinetics
12.3 Pharmacokinetics Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Plasma concentrations of the parent drug, leflunomide, have been occasionally seen at very low concentrations. Studies of the pharmacokinetics of leflunomide have primarily examined the plasma concentrations of the active metabolite, teriflunomide. Absorption Following oral administration, peak teriflunomide concentrations occurred between 6 to 12 hours after dosing. Due to the very long half-life of teriflunomide (18 to 19 days), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state teriflunomide concentrations. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require about two months of dosing. The resulting plasma concentrations following both loading doses and continued clinical dosing indicate that plasma teriflunomide concentrations are dose proportional. Effect of Food Coadministration of leflunomide tablets with a high fat meal did not have a significant impact on teriflunomide plasma concentrations. Distribution Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration. Elimination Teriflunomide, the active metabolite of leflunomide, has a media